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Guillaume LUCAS





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31 publication(s) since Janvier 1996:


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Abstract:
We investigated, using single-unit recordings in chloral hydrate-anaesthetized rats, the role of serotonin 4 (5-HT4) receptors in the control of dorsal raphe nucleus (DRN) 5-HT neuron activity. About one-half (36) of the 76 neurons recorded were affected by either the preferential 5-HT4 agonist cisapride (500 and 1000 micro g/kg, i.v.) or the selective 5-HT4 antagonist, GR 125487 (200- 2000 micro g/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 +/- 0.1 Hz) than non-responders (1.31 +/- 0.1 Hz). The firing rate of responding 5-HT neurons was enhanced dose-dependently by cisapride (+47 and +94% at 500 and 1000 micro g/kg, respectively), an effect abolished by GR 125487 (500 micro g/kg) and reduced by the 5-HT4 antagonist, SDZ 205557 (500 micro g/kg, i.v). Conversely, GR 125487 induced a dose-dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 micro g/kg. In a separate set of experiments, the selective 5-HT4 agonist, prucalopride (500 micro g/kg, i.v), increased the firing activity (+35%) of 5-HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 micro g/kg, i.v.) suppressed this effect. These results indicate that 5-HT4 receptors exert both a tonic and a phasic, positive, frequency-related control on DRN 5-HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field.




03/2002 | Neuropsychopharmacology   IF 6.5
5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum.
Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S, Esposito E, Spampinato U

Abstract:
In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin(2A) (5-HT(2A)) and serotonin(2C/2B) (5-HT(2C/2B)) receptors in the effects induced by amphetamine and morphine on dopaminergic (DA) activity within the mesoaccumbal and nigrostriatal pathways. The increase in DA release induced by amphetamine (2 mg/kg i.p.) in the nucleus accumbens and striatum was significantly reduced by the selective 5-HT(2A) antagonist SR 46349B (0.5 mg/kg s.c.), but not affected by the 5-HT(2C/2B) antagonist SB 206553 (5 mg/kg i.p.). In contrast, the enhancement of accumbal and striatal DA output induced by morphine (2.5 mg/kg s.c.), while insensitive to SR 46349B, was significantly increased by SB 206553. Furthermore, morphine (0.1-10 mg/kg i.v.)-induced increase in DA neuron firing rate in both the ventral tegmental area and the substantia nigra pars compacta was unaffected by SR 46349B (0.1 mg/kg i.v.) but significantly potentiated by SB 206553 (0.1 mg/kg i.v.). These results show that 5-HT(2A) and 5-HT(2C) receptors regulate specifically the activation of midbrain DA neurons induced by amphetamine and morphine, respectively. This differential contribution may be related to the specific mechanism of action of the drug considered and to the neuronal circuitry involved in their effect on DA neurons. Furthermore, these results suggest that 5-HT(2C) receptors selectively modulate the impulse flow-dependent release of DA.




03/2001 | Eur J Neurosci   IF 2.8
Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function.
Lucas G, Di Matteo V, De Deurwaerdere P, Porras G, Martin-Ruiz R, Artigas F, Esposito E, Spampinato U

Abstract:
In this study we investigated, using in vivo microdialysis and single unit recordings, the role of serotonin4 (5-HT4) receptors in the control of nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity. In freely moving rats, the 5-HT4 antagonist GR 125487 (1 mg/kg, i.p.), without effect on its own, significantly reduced the enhancement of striatal DA outflow induced by 0.01 (-35%) and 0.1 (-66%), but not 1 mg/kg, s.c. haloperidol (HAL). Intrastriatal infusion of GR 125487 (1 microM) had no influence on basal DA outflow, but attenuated (-49%) the effect of 0.01 mg/kg HAL. Systemic administration of GR 125487 modified neither basal nor 0.01 mg/kg HAL-stimulated accumbal DA outflow. In halothane-anaesthetized rats, 1 or 10 mg/kg GR 125487, without effect by itself, failed to modify the changes in accumbal and striatal DA outflow elicited by electrical stimulation (300 microA, 1 ms, 20 Hz, 15 min) of the dorsal raphe nucleus. Finally, GR 125487 (444 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra or the ventral tegmental area, reduced HAL-stimulated (1--300 microg/kg, i.v.) impulse flow of nigrostriatal DA neurons only. These results indicate that 5-HT4 receptors exert a facilitatory control on both striatal DA release and nigral DA neuron impulse flow only when nigrostriatal DA transmission is under activated conditions. Furthermore, they indicate that the striatum constitutes a major site for the expression of the control exerted by 5-HT4 receptors on DA release. In contrast, 5-HT4 receptors have no influence on mesoaccumbal DA activity in either basal or activated conditions.




Abstract:
Several observations indicate that 5-HT1A receptors found on a long neuronal feedback loop, originating from the medial prefrontal cortex, regulate 5-HT neuronal firing. In the present study, the muscarinic (M) receptor antagonists atropine and scopolamine as well as the M2 receptor antagonist AF-DX 116, but not the preferential M1 receptor antagonist pirenzepine, reduced the suppressant effect of the 5-HT1A receptor agonist 8-OH-DPAT on the spontaneous firing activity of rat dorsal raphe 5-HT neurons. Moreover, AF-64A-induced lesions of cholinergic neurons directly in the medial prefrontal cortex and after its i.c.v. injection attenuated the effect of 8-OH-DPAT. Finally, the NMDA receptor antagonist (+)MK-801 and the GABA(B) receptor antagonist SCH-50911, but not the GABA(A) receptor antagonist (-)bicuculline, dampened the latter response. The present study unveiled a key role for the cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons.




23/08/2000 | Neuropharmacology   IF 4.2
Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated.
Lucas G, De Deurwaerdere P, Porras G, Spampinato U

Abstract:
In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibitors citalopram and fluoxetine were used to mobilize endogenous 5-HT. In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (-25 and -15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 microM concentration, but enhanced DA release after its perfusion at 25 and 100 mircroM concentrations (+27% and +67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 microM citalopram. In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 microM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+31% and +30% for citalopram and fluoxetine, respectively). These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.




08/2000 | J Neurochem   IF 4.6
Striatal serotonin receptors and dopamine release: Reply.
Lucas G, Spampinato U

Abstract:





Abstract:
This study investigated, using microdialysis in freely-moving rats, the role of serotonin (5-HT) and 5-HT(2) receptor subtypes in the enhancement of striatal dopamine (DA) release induced by various doses of haloperidol. The subcutaneous injection of 0.01, 0.1 or 1 mg/kg haloperidol dose-dependently increased DA outflow (160, 219 and 230% of baseline, respectively). The effect of 0.01 mg/kg haloperidol was, respectively, potentiated by the 5-HT uptake inhibitor citalopram (1 mg/kg, s.c.; +35%) and reduced by the 5-HT(1A) receptor agonist 8-OH-DPAT (0.025 mg/kg, s.c.; -32%). Also, it was reduced by the 5-HT(2A) antagonist SR 46349B (0.5 mg/kg, s.c. ; -40%) or by the 5-HT(2A/2B/2C) antagonist ritanserin (1.25 mg/kg, i.p.; -34%), and potentiated by the 5-HT(2B/2C) antagonist SB 206553 (5 mg/kg, i.p; +78%). Further, only this latter compound significantly modified basal dopamine release by itself (+26%). Dopamine released by 0.1 mg/kg haloperidol was enhanced (+100%) by citalopram, decreased (-61%) by SR 4634B, but unaltered by SB 206553. Finally, none of the compounds used were able to modify the enhancement of dopamine release induced by 1 mg/kg haloperidol. These results show that central 5-HT(2A) and 5-HT(2C) receptors exert an opposite (respectively excitatory and inhibitory) influence on DA release. Moreover, they suggest that the 5-HT(2A)-dependent modulation depends on the degree of central DA receptor blockade.




Abstract:
This study investigated, using in vivo microdialysis in the striatum of freely moving rats, the role of striatal serotonin2A (5-HT2A) and 5-HT2C receptor subtypes in the modulation of dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) outflow, both in basal conditions and under activation induced by subcutaneous administration of 0.01 mg/kg haloperidol. The different 5-HT2 agents used were applied intrastriatally at a 1 microM concentration through the microdialysis probe. Basal DA efflux was enhanced (27%) by the 5-HT2A/2B/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) and reduced (-30%) by the 5-HT2B/2C antagonist SB 206553. It was unaffected by infusion of the 5-HT2A antagonist SR 46349B. The effect of DOI was abolished by SB 206553 but not modified by SR 46349B. Haloperidol-stimulated DA efflux (65-70%) was reduced by both SR 46349B (-32%) and the 5-HT2A/2B/2C antagonist ritanserin (-30%) but not affected by SB 206553. Conversely, the effect of haloperidol was potentiated (22%) when DOI was coperfused with SB 206553. Also, haloperidol-stimulated DOPAC outflow (40-45%) was reduced (-20%) by SR 46349B and potentiated (25%) by the combination of SB 206553 with DOI. These results indicate that striatal 5-HT2A receptors, probably through activation of DA synthesis, positively modulate DA outflow only under activated conditions. In contrast, striatal 5-HT2C receptors exert a facilitatory control on basal DA efflux, which appears to be both tonic and phasic.




05/1997 | Psychopharmacology (Berl)   IF 3.2
8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release.
Lucas G, Bonhomme N, De Deurwaerdere P, Le Moal M, Spampinato U

Abstract:
In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT1A agonist 8-OH-DPAT or the 5-HT2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum.




01/1997 | J Neurochem   IF 4.6
Serotonin stimulation of 5-HT4 receptors indirectly enhances in vivo dopamine release in the rat striatum.
De Deurwaerdere P, L'hirondel M, Bonhomme N, Lucas G, Cheramy A, Spampinato U

Abstract:
Serotonin (5-HT) applied at 1, 3, and 10 microM into the striatum of halothane-anesthetized rats by in vivo microdialysis enhanced dopamine (DA) outflow up to 173, 283, and 584% of baseline values, respectively. The 5-HT effect was partially reduced by 1 or 10 microM GR 125,487, a 5-HT4 antagonist, and by 100 microM DAU 6285, a 5-HT3/4 antagonist, whereas the 5-HT1/2/6 antagonist methiothepin (50 microM) was ineffective. In the presence of tetrodotoxin the effect of 1 microM 5-HT was not affected by 5-HT4 antagonists. In addition, tetrodotoxin abolished the increase in DA release induced by the 5-HT4 agonist (S)- zacopride (100 microM). In striatal synaptosomes, 1 and 10 microM 5-HT increased the outflow of newly synthesized [3H]DA up to 163 and 635% of control values, respectively. The 5-HT4 agonists BIMU 8 and (S)-zacopride (1 and 10 microM) failed to modify [3H]DA outflow, whereas 5- methoxytryptamine (5-MeOT) at 10 microM increased it (62%). In prelabeled [3H]DA synaptosomes, 1 microM 5-HT, but not (S)-zacopride (1 and 10 microM), increased [3H]DA outflow. DAU 6285 (10 microM) failed to modify the enhancement of newly synthesized [3H]DA outflow induced by 5-MeOT or 5-HT (1 microM), whereas the effect of 5-HT was reduced to the same extent by the DA reuptake inhibitor nomifensine (1 microM) alone or in the presence of DAU 6285. These results show that striatal 5-HT4 receptors are involved in the 5-HT-induced enhancement of striatal DA release in vivo and that they are not located on striatal DA terminals.